As many tumor antigens are expressed as self-antigens, thymic and peripheral tolerance mechanisms act to eliminate high avidity tumor specific T cells. This is a proposal to continue experiments designed to increase the efficacy of tumor eradication by low avidity CD8+ cytolytic T lymphocytes (CTL) directed towards a tumor associated antigen. The underlying hypothesis of this proposal is that we could greatly enhance tumor immunotherapy by developing protocols that optimize the effector capability and longevity of the predominantly low avidity tumor antigen specific CDS T cells that remain within the T cell receptor repertoire of the tumor bearing host. These experiments will use a murine tumor model in which pancreatic insulomas expressing the influenza hemagglutinin (HA) arise spontaneously, RIP-Tag2-HA mice. Also available for these studies are 2 different CDS TCP transgenic lines specific for the same Kd-restricted HA epitope, yet, which have substantially different affinities, Clone 1 (low affinity) and Clone 4 TCR (high affinity); and a CD4 TCP transgenic line specific for an l-Ed restricted HA epitope, SFE. Whereas Clone 4 was derived from a conventional mouse that was immunized with influenza, Clone 1 was derived from an InsHA mouse in which tolerance to HA was induced by the presence of HA expressed in pancreatic islets. Aim 1 will develop protocols to enhance the efficacy of tumor eradication by low avidity Clone 1 cells. Strategies to be tested include; repeated vaccination, provision of IL-15, low dose irradiation, elimination of Tregs, and excision of lymph nodes that drain the tumor. Aim 2 will examine when, where and how HA specific CD4 helper cells assist Clone 1 T cells in tumor eradication. Also, a major goal of this aim will be to determine whether CD4 help for tumor eradication must be specific for a tumor antigen, rather than an antigen present in the tumor vaccine. These experiments will assist in the development of vaccines and immunotherapy of cancer. They will also provide insight into how we may boost immunity to persistently expressed antigens.